Increasing Incidence of Coccidioidomycosis in the United StatesReviewed by Jonathan Li, MD

Coccidioidomycosis is a fungal infection caused by the inhalation of Coccidioides spp. organisms that are endemic to the soil of southwestern United States, northern Mexico, and regions of Central and South America. The most common presentation is a self-limited pulmonary infection, but a small subset will progress to a severe pneumonia or disseminated disease. In the March 29 issue of the Morbidity and Mortality Weekly Report, an analysis by the Centers for Disease Control and Prevention described the changing incidence of coccidioidomycosis based on data voluntarily reported by states to the National Notifiable Diseases Surveillance System.

Between 1998 and 2011, the results showed a significant increase in rates of reported coccidioidomycosis, from 5 per 100,000 to 43 per 100,000. In total, there were more than 111,000 cases from 28 states, but the majority of cases clustered in just a few endemic states: Arizona (66 percent), California (31 percent), Nevada (1 percent), New Mexico (1 percent), and Utah (1 percent). The annual increase was 16 percent in Arizona and 13 percent in California even after adjusting for changes in population size and age/sex distribution. Coccidioidomycosis represented the second most common nationally notifiable condition in Arizona and the fourth most common in California.

This report likely underestimates the national incidence of coccidioidomycosis given the voluntary nature of the case reporting and the inconsistent reporting requirements among the states. This study did not investigate the potential causes for this increase, but possibilities include environmental changes, increased disruption of soil such as through construction, changes in surveillance methods, and increased awareness and testing.

Regardless of the reason behind the rising incidence, this report should raise the awareness of this disease for clinicians treating patients who live in or have recently returned from endemic regions.

Bloodstream infections are a significant cause of morbidity and mortality among critically ill children. Daily chlorhexidine bathing was recently shown to be safe and effective at reducing hospital-acquired bloodstream infections among critically ill adults. However, it is unknown if chlorhexidine bathing is similarly effective and well tolerated among pediatric patients.

To answer this question, researchers from five hospitals in the United States—whose findings appear in the March issue of The Lancet—randomized 10 pediatric intensive-care units to perform daily washing of patients with either standard bathing practices or using a cloth impregnated with 2 percent chlorhexidine gluconate (CHG) for six months. Units then switched to the alternate bathing method for a second six-month period. The primary outcome of the study was incidence of bacteremia per 1,000 patient-days at risk.

In a per-protocol analysis, children who received CHG (n=667) had a 36 percent lower risk of bacteremia compared to children who received standard therapy (n=1,326, adjusted incidence rate ratio (aIRR) 0.64, 95 percent CI 0.42-0.98). Treated children also had a reduction in central-line associated infections compared to controls (aIRR 0.68, 95 percent CI 0.35-1.31). The reduction in infections was observed primarily for Gram-positive organisms. There was no difference in mortality between the two groups, and there were no serious study-related adverse events reported.

The primary weakness of this study is that a large number of eligible patients did not consent to participate in the trial, so the intention-to-treat analysis did not yield significant findings. However, the authors argue that the estimated effect of CHG bathing was similar in the intention-to-treat and per-protocol analyses, suggesting that their findings are clinically relevant. When considered in the context of other recent studies, these results support an emerging consensus that CHG bathing is an effective and safe means to reduce bacteremia in critically ill patients.

Combination Therapy for Cryptococcal Meningitis: An End to the Debate?Reviewed by George R. Thompson III, MD

Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis (CM) but has not been shown to reduce mortality compared to amphotericin B (AMB) monotherapy. The overlapping toxicities of these antifungals when used in combination with an unproven benefit has thus led some practitioners to prescribe amphotericin B alone.

In the April 4 issue of the New England Journal of Medicine, researchers describe a prospective randomized evaluation of induction therapy for cryptococcal meningitis in 299 patients with HIV. Patients were randomized to one of three groups: AMB alone, AMB plus flucytosine, or AMB plus fluconazole.

There were fewer deaths by day 14 in the group receiving amphotericin plus flucytosine than those who received amphotericin B alone (p=0.08) and a statistically significant difference in survival at 70 days (p=0.04). Combination therapy with fluconazole had no effect on survival compared to amphotericin B alone (p=0.42). Adverse effects were similar between groups, although leukopenia was more common in the AMB/flucytosine group.

These results confirm smaller studies showing more rapid clearance of the cerebrospinal fluid (CSF) in patients treated with AMB plus flucytosine compared to other regimens. This microbiologic parameter has now shown an association with patient mortality and provides additional evidence that quantitative monitoring of the CSF may be helpful and optimization of antifungal regimens is essential to improve patient outcomes.

This study provides outcome-based evidence for the use of combination therapy in cryptococcal meningitis and should help end the debate regarding the addition of flucytosine to AMB during treatment of CM.

In the April issue of The American Journal of Medicine, a community-wide study of eight clinics in Colorado sought to evaluate how clinical pathways and patient education for eight common infections—nonspecific upper respiratory infection (URI), acute bronchitis, acute rhinosinusitis, pharyngitis, acute otitis media, urinary tract infection, skin and soft tissue infection (cellulitis or cutaneous abscess), and community-acquired pneumonia—might affect antibiotic prescription patterns over the course of one year.

Clinics were randomized into two groups: Four study clinics where the pathways and patient education materials were used, and four control clinics without intervention. Each “pathway” was a one-page algorithm designed to help providers determine whether to prescribe an antibiotic, and if indicated, the optimal one to use and the shortest appropriate duration of therapy. The primary outcomes were change over time in antibiotic prescriptions for non-pneumonia acute respiratory infections and change over time in broad-spectrum antibiotic prescriptions for all clinical pathway conditions. There were more providers (46 vs. 34) and more patients (52,766 vs. 48,881) in the study group than the control group.

The proportion of acute respiratory infections for which an antibiotic was prescribed decreased in the study group from 42.7 percent of cases during the baseline period to 37.9 percent during the intervention period (P < .0001, relative reduction 11.2 percent). The effect was mostly due to a reduction in prescriptions for URI and acute bronchitis. Over the same period, the control group had a relative reduction of only 2.8 percent. For all eight infections, prescriptions of broad-spectrum antibiotics in the study group decreased from 26.4 percent to 22.6 percent of cases (14.4 percent relative reduction) (P < .0001) and from 20.0 percent to 19.4 percent in the control group (3.0 percent relative reduction) (P = .35).

This study shows antibiotic stewardship can be successfully employed in clinics in the short term. It also provides a template for evaluating strategies to obtain a durable reduction of outpatient antibiotic prescriptions.